Friday, December 2, 2016

Male versus female stress responses may explain sex differences in diseases

The finding by USC researchers (University of Southern California Health News, 12/02/2016 may explain how Alzheimer’s and Parkinson’s affect men and women.
The differences in how male and female fruit flies resist and adapt to oxidative stress may shed new light on how age–related diseases such as Alzheimer’s and Parkinson’s affect men and women differently.

Through a series of tests, USC researchers found that female fruit flies were better able to respond to stress caused by a common oxidant, hydrogen peroxide (produced naturally in the body for cell signaling and to combat infection), than males. However, males were better able to adapt to another oxidant, paraquat, a common herbicide.

Both oxidants have been implicated in human diseases. Elevated levels of hydrogen peroxide are found in patients suffering from a stroke, a heart attack or Alzheimer’s disease. Paraquat is one of the environmental toxins that can damage the neurons involved in Parkinson’s disease, which attacks the nervous system.

The male and female responses to the stress seem to differ in part because of a protein, Lon protease, that localizes to mitochondria, the researchers found.

The researchers’ findings, published in the journal Current Biology on Dec. 1, indicate the need for further investigation into sex–based differences in the biological responses of men and women, particularly as scientists consider new ways to treat age–related diseases, Tower said.

Laura C.D. Pomatto, Caroline Carney, Brenda Shen, Sarah Wong, Kelly Halaszynski, Matthew P. Salomon3, Kelvin J.A. Davies, John Tower.  The Mitochondrial Lon Protease Is Required for Age-Specific and Sex-Specific Adaptation to Oxidative Stress. Current Biology.  In press.

•Female-specific H2O2 and male-specific paraquat stress adaptation require Lon
•Sex-specific expression of Lon protein isoforms
•Sex-specific Lon expression and stress adaption are regulated by transformer
•Sex-specific expression of Lon isoforms is observed in mammalian tissues

Multiple human diseases involving chronic oxidative stress show a significant sex bias, including neurodegenerative diseases, cancer, immune dysfunction, diabetes, and cardiovascular disease. However, a possible molecular mechanism for the sex bias in physiological adaptation to oxidative stress remains unclear. Here, we report that Drosophila melanogaster females but not males adapt to hydrogen peroxide stress, whereas males but not females adapt to paraquat (superoxide) stress. Stress adaptation in each sex requires the conserved mitochondrial Lon protease and is associated with sex-specific expression of Lon protein isoforms and proteolytic activity. Adaptation to oxidative stress is lost with age in both sexes. Transgenic expression of transformer gene during development transforms chromosomal males into pseudo-females and confers the female-specific pattern of Lon isoform expression, Lon proteolytic activity induction, and H2O2 stress adaptation; these effects were also observed using adult-specific transformation. Conversely, knockdown of transformer in chromosomal females eliminates the female-specific Lon isoform expression, Lon proteolytic activity induction, and H2O2 stress adaptation and produces the male-specific paraquat (superoxide) stress adaptation. Sex-specific expression of alternative Lon isoforms was also observed in mouse tissues. The results develop Drosophila melanogaster as a model for sex-specific stress adaptation regulated by the Lon protease, with potential implications for understanding sexual dimorphism in human disease. 

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